Despite five decades of research concerning cardiac arrest/cardiopulmonary resuscitation (CA/CPR), clinical outcome remains poor. Only 5% of individuals who suffer CA are successfully resuscitated to the extent that they return to normal, productive lives, and neuropsychological deficiencies remain prevalent in the remaining 95% of patients. One reason why outcome from CA/CPR remains poor is that mechanisms of cell injury and targets for neuroprotection have been poorly elucidated. Women are at lower risk than men for cardiovascular disease yet cerebral ischemic events occur in both sexes. The role of estrogens in humans is controversial;however, we demonstrated in the past funding period that female mice have better outcome than males after CA/CPR. We now focus on potential transcriptional mechanisms by which estradiol exerts its neuroprotective action in CA/CPR. Using a microarray technique, we identified gene candidates that are induced/suppressed by estrogen under ischemic conditions. One provocative candidate, the neuropeptide cocaine and amphetamine regulated transcript (CART) is strongly induced by cerebral ischemia and provides robust neuroprotection. We propose to determine if CART is an important mechanism by which estradiol reduces neuronal injury after CA/CPR and whether CART exerts its neuroprotective effects via the extracellular regulated kinase (ERK) pathway. While most research has focused on understanding the role of estradiol in ischemia, the role of androgens in ischemic sensitivity is unknown. We propose to study testosterone, a sex steroid with potential to exacerbate brain injury from CA/CPR. Our preliminary data suggests that testosterone increases and castration decreases neuronal injury after CA/CPR, and we hypothesize that androgens signal through their cognate receptor to orchestrate neuronal ischemic death. Thus, this proposal will focus on novel mechanisms by which male and female sex steroids shape brain outcome after CA/CPR. Aim 1 determines if estradiol enhances CART expression and suppresses ERK activation after CA/CPR in a region-specific manner. Aim 2 determines if CART protection requires signaling via estrogen receptor beta. Aim 3 determines if androgens play an important role in neuropathological and functional recovery after CA/CPR. Finally, Aim 4 determines if the androgen receptor is essential to how androgen enhances post arrest brain injury.